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A Strain-Specific Inhibitor of Receptor-Bound HIV-1 Targets a Pocket Near the Fusion Peptide and Offers a Template for Drug Design

53 Pages Posted: 31 Jul 2020 Publication Status: Published

See all articles by Gabriel Ozorowski

Gabriel Ozorowski

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

Jonathan L. Torres

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

Diogo Santos-Martins

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

Stefano Forli

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

Andrew B. Ward

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

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Abstract

Disruption of viral fusion represents a viable, albeit under-explored, target for HIV therapeutics. While studying the receptor-bound envelope glycoprotein conformation by cryo-EM, we identified a pocket near the base of the trimer containing a bound detergent molecule and performed in silico drug screening using a library of drug-like and commercially available molecules. After down-selection, we solved cryo-EM structures that validated binding of two small molecule hits in very similar manners to the predicted binding poses, including interactions with aromatic residues within the fusion peptide. One of the molecules demonstrated low micromolar inhibition of the autologous virus by utilizing a very rare phenylalanine in the fusion peptide and stabilizing the surrounding region. This work demonstrates that small molecules can target the fusion process, providing a new target for anti-HIV therapeutics, and highlights the need to explore how fusion peptide sequence variations affect receptor-mediated conformational states across diverse HIV strains.

Suggested Citation

Ozorowski, Gabriel and Torres, Jonathan L. and Santos-Martins, Diogo and Forli, Stefano and Ward, Andrew B., A Strain-Specific Inhibitor of Receptor-Bound HIV-1 Targets a Pocket Near the Fusion Peptide and Offers a Template for Drug Design (July 2020). Available at SSRN: https://ssrn.com/abstract=3645425 or http://dx.doi.org/10.2139/ssrn.3645425
This version of the paper has not been formally peer reviewed.

Gabriel Ozorowski

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

Jonathan L. Torres

The Scripps Research Institute - Department of Integrative Structural and Computational Biology ( email )

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

Diogo Santos-Martins

The Scripps Research Institute - Department of Integrative Structural and Computational Biology ( email )

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

Stefano Forli (Contact Author)

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

10550 North Torrey Pines Road
La Jolla, CA 92037
United States

Andrew B. Ward

The Scripps Research Institute - Department of Integrative Structural and Computational Biology

United States

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